Extracellular vesicle transport across the BBB

The brain is a highly sensitive organ, which is protected from noxious agents circulating in the blood stream by the so-called blood-brain barrier (BBB). The BBB also ensures a steady and adequate supply of the required nutrients to the brain cells. The main component of the BBB in most vertebrates and in humans are the brain endothelial cells, which line the inside of the blood capillaries in the brain. This specialized cell layer is characterized by extremely tight cell-cell junctions and strictly regulates the passage of ions, molecules, vesicles, pathogens and (immune) cells from the bloodstream into the brain. The control and regulation of these transport mechanisms is essential for brain function, and aberrations of them can be a trigger or consequence of common diseases such as Alzheimer`s disease and stroke. The molecular mechanisms that transport key molecules such as glucose, amino acids or transferrin across the BBB have been studied in recent decades. Significant efforts were taken to exploit these transport mechanisms for the delivery of drugs into the central nervous system. Nonetheless, most pharmaceutical compounds fail to reach the diseased target area in the brain in sufficient quantities due the restrictions set by the BBB. A transport pathway which remains elusive yet mediates the exchange of extracellular vesicles (EVs) between blood stream and brain. Since several years there is evidence that EVs are able to cross the BBB in both directions, but no molecular mechanisms or determinants have been identified so far. In the present project, we will use a variety of different experimental approaches to identify the molecular mechanisms and associated cellular factors involved in EV transport across the BBB. Among others, we will employ sophisticated in vitro cell culture models of the BBB based on human induced pluripotent stem cells, high-resolution microscopy techniques and state-of-the-art proteomic analysis. To investigate disease-relevant changes in EV transport mechanisms, EVs derived from selected tumor cells or stroke models will also be applied and studied. The obtained data will expand the overall understanding of BBB function, and may have relevance to brain diseases, as well as future diagnostic and therapeutic developments.

No additional funding sources recorded.